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PubMedDate not supplied

Phase 1 trial of subcutaneous IL-6 in patients with refractory cancer: clinical and biologic effects.

The authors evaluated the clinical and biologic effects of human recombinant interleukin-6 (rhIL-6) in patients with refractory cancer. A phase 1 trial using escalating doses of rhIL-6 (1-50 microg x kg(-1) x d(-1), Monday through Friday for 4 weeks) was performed in 30 patients. Toxicity was moderate and the maximum tolerated dose was determined to be 25 microg x kg(-1)x d(-1) based on cardiac and neurocortical toxicity in one patient each and thrombocytosis (platelets > 800,000/microL) in three patients. One patient with non-small-cell lung cancer had a partial response after three cycles of therapy. The biologic effects of rhIL-6 included anemia and dose-related thrombocytosis. Various proinflammatory activities were induced and included dose-related cyclical increases in peripheral blood monocytes and the CD14+/CD45RB+ +/- CD16C+ mononuclear cell populations. These increases were accompanied by increased levels of C-reactive protein, serum neopterin, and type I soluble tumor necrosis factor receptor. In contrast, rhIL-6 did not affect lymphocyte numbers or function (cytotoxicity, cytokine levels, immunoglobulin levels), with the possible exception of IL-2Ralpha mRNA induction in peripheral blood lymphocytes. rhIL-6 has pleiotropic proinflammatory actions in vivo and moderate toxicity when administered as long-term therapy.

Acute-Phase Reaction↗
PubMed1989

Relationship between results of laboratory tests and inflammatory activity assessed by colonoscopy in children and adolescents with ulcerative colitis and Crohn's colitis.

The relationship between the results of nine laboratory tests and inflammatory activity in the colon assessed macroscopically (macro) and histologically (hist) has been studied in 60 children and adolescents, 36 with ulcerative colitis (UC), and 24 with Crohn's colitis (CC). The mean duration of disease was 38 months. Eleven patients were newly diagnosed and not treated. Special attention was paid to severe and extensive colitis (SEC), in other words, moderate or severe inflammation in at least six of eight colon segments. A significant correlation was found between some laboratory parameters and the inflammatory activity of colonic mucosa. In UC, the following abnormal laboratory test results only occurred in SEC/macro: thrombocytosis, low serum albumin, and high serum orosomucoid. The combination of low serum iron and low or normal total iron binding capacity (TIBC) occurred in seven cases, six of whom had SEC/macro. Eleven of the 17 patients with SEC/macro had at least one of these four test results. SEC/hist was indicated only by thrombocytosis and high orosomucoid. In CC, a combination of low serum iron and low TIBC only occurred in SEC/macro. Thirteen of 36 patients with UC (36%) and four of 24 with CC (17%) had no abnormal test results.

Adolescent↗
PubMed2007

JAK-2 mutations and their relevance to myeloproliferative disease.

PURPOSE OF REVIEW: The identification of the JAK2V617F allele greatly improved our understanding of the molecular pathogenesis of myeloproliferative disorders. This review focuses on recent studies offering new genetic, biochemical, and functional insight into the role of JAK2V617F in the pathogenesis of these disorders. RECENT FINDINGS: JAK2V617F mutations are present in almost all patients with polycythemia vera, and in approximately half of those with essential thrombocytosis and myelofibrosis. JAK2V617F has constitutive tyrosine kinase activity, and is able to transform hematopoietic cells and activate JAK-STAT signaling when co-expressed with homodimeric type I cytokine receptors. Murine bone marrow transplant experiments demonstrate that JAK2V617F is sufficient for the development of polycythemia vera in recipient mice. These results suggested that JAK-STAT pathway activation might contribute to the pathogenesis of JAK2-negative myeloproliferative disorders, and led to the discovery of an activating mutation in the thrombopoietin receptor in JAK2-negative myelofibrosis and essential thrombocytosis. SUMMARY: The discovery of the JAK2V617F allele represents an important advance in our understanding of the molecular pathogenesis of myeloproliferative disorders, though many questions remain regarding the role of a single allele in three clinically distinct disorders, the mechanism of activation of JAK2V617F, and the pathogenesis of JAK2-negative myeloproliferative disorders.

Humans↗
PubMed1986

Abnormalities of von Willebrand factor in myeloproliferative disease: a relationship with bleeding diathesis.

We studied factor VIII related properties in 24 patients with increased platelet number. Twenty-one were affected by myeloproliferative disorders (eight had polycythaemia vera, 13 had essential thrombocythaemia) and three had secondary thrombocytosis. Normal levels of VIII:C and VIIIR:Ag were found while a significant (P less than 0.05) decrease of VIIIR:RCOF (43 +/- 13%) related to a lack of larger multimers of VWF (39 +/- 12%) was observed in 57% of patients with myeloproliferative disorders. A normal VWF pattern was found in the three patients with secondary thrombocytosis. The highest incidence of VWF abnormalities occurred in patients with essential thrombocythaemia (70%) in comparison with polycythaemic patients (38%). A significant (P less than 0.03) correlation between platelet count and the values of both VIIIR:RCOF and VWF multimeric pattern was observed only in patients with polycythaemia vera. The lowest levels of VIIIR:RCOF and the greatest loss of larger VWF multimers (less than 30%) were observed in two patients who presented bleeding symptoms at the time of study and a prolonged bleeding time. In addition, the relationship between VWF pattern and bleeding diathesis was supported by the fact that 75% of the patients with VWF abnormalities had bleeding history.

Adult↗
PubMed1993

Clinical, haematological and cytogenetic features in 24 patients with structural rearrangements of the Q arm of chromosome 3.

To determine the frequency and clinical significance of acquired abnormalities of chromosome 3 at q21 and q25-26 in haematological malignancy, we reviewed the haematological and cytogenetic features of 24 patients with a 3q rearrangement identified amongst 1200 cases with clonal cytogenetic abnormalities detected at our institutions during a 12-year period. Thirteen patients presented with de novo acute myeloid leukaemia (AML), 10 with myelodysplasia (MDS) and one in blast phase of chronic myelogenous leukaemia. Twenty patients (83%) had megakaryocytic dysplasia and 14 (58%) had normal or increased numbers of megakaryocytes, but only four patients (16%) had absolute thrombocytosis > 500 x 10(9)/l (three with AML, one with MDS transforming to AML). A review of 205 cases of AML investigated in our institutions between 1985 and 1990 for whom cytogenetic results were obtained revealed that a platelet count > 500 x 10(9)/l at presentation was highly suggestive of an underlying 3q abnormality. A limited review of the literature on this subject confirmed that 15-20% of patients with a 3q abnormality will have thrombocytosis. The response of these patients to conventional antileukaemic therapy is uniformly poor, despite haematological and clinical differences between the subtypes of 3q rearrangements.

Acute Disease↗
PubMed1993

Vascular complications of essential thrombocythaemia: a link to cardiovascular risk factors.

Essential thrombocythaemia (ET) is a myeloproliferative disorder characterized by absolute thrombocytosis and increased incidence of thrombosis and haemorrhage. We report higher morbidity in patients with ET due to arterial ischaemic complications when cardiovascular risk factors are present. In this retrospective analysis of 46 patients, arterial complications occurred in 20/46 patients (43.4%); patients with cardiovascular risk factors, especially cigarette smoking, had more than twice as many arterial complications than patients without risk factors (62.5% v 22.7%, P < 0.05). Neither age, gender nor degree of thrombocytosis were linked to the number of complications. In contrast, we observed no association between cardiovascular risk factors and venous thrombosis or haemorrhagic complications of ET.

Adult↗
PubMed2005

Thrombosis and haemorrhage in polycythaemia vera and essential thrombocythaemia.

Despite decades of clinical and laboratory research, relatively little has been accomplished concerning the pathogenesis as well as the identification of risk factors for thrombosis and bleeding in myeloproliferative disorders. In polycythaemia vera, the pro-thrombotic effect of an elevated haematocrit is well established. In contrast, thrombocytosis per se has not been similarly incriminated in essential thrombocythaemia. In both conditions, advanced age and the presence of a prior event identify thrombosis-prone patients. There is increasing evidence to suggest an additional role by leucocytes that might partly explain the antithrombotic effects of myelosuppressive therapy. A substantial minority of affected patients display reduced levels of high molecular weight von Willebrand protein in the plasma during extreme thrombocytosis and it is believed that this might explain the bleeding diathesis of such patients. Recent controlled studies support the therapeutic value of hydroxyurea and aspirin in essential thrombocythaemia and polycythaemia vera, respectively. The current communication will address the incidence, phenotype, pathogenesis, risk factors, prevention, and treatment of both thrombosis and haemorrhage in these disorders.

Aged↗
PubMed2005

Mycoplasma pneumoniae infections in Australian children.

OBJECTIVES: To describe the epidemiology, clinical features and outcome of Mycoplasma pneumoniae infection in children presenting to a tertiary children's hospital. METHODS: Sixty-three month retrospective review of serologically diagnosed M. pneumoniae infections. RESULTS: There were 76 children, 42 boys and 34 girls, mean age 6.3 +/- 3.5 years. The age group most commonly affected was 5-9 years, followed by children 1-5 years. More than half of the patients had failed to respond to antibiotics before referral. The commonest presentation was with cough and fever. Coryza, diarrhoea, vomiting, tachypnoea and recession were significantly more common in children less than 5 years than in children 5-15 years. Hospitalized patients were more likely than non-hospitalized patients to have respiratory distress with recession and wheeze. Radiographic findings were non-specific. Thrombocytosis was found in 29 (41.4%) of 70 children studied. CONCLUSION: The clinical features of M. pneumoniae infection were different in children less than 5 years than in children aged 5-9 years. The presence of thrombocytosis in 40% of the cases has not previously been reported in children.

Adolescent↗
PubMedDate not supplied

Hematologic changes after splenectomy for cytoreduction: implications for predicting infection and effects on chemotherapy.

Postsplenectomy leukocytosis and thrombocytosis are common findings in trauma patients. The intent of this study is to describe postsplenectomy hematologic changes in gynecological oncology surgery and subsequent chemotherapy. We performed a retrospective record review of gynecological oncology patients at our institutions. Postsurgical hematologic changes, infectious morbidity, and pre- and post-chemotherapy hematologic changes were noted. Data were analyzed using repeated measures analysis of variance. We identified 27 patients who underwent cytoreductive surgery with splenectomy. Thirteen patients with splenectomy had postoperative chemotherapy data available, and we matched these patients with 13 control patients who underwent cytoreduction surgery without splenectomy and postoperative chemotherapy. Nine of the 27 splenectomy patients had documented infectious morbidity. There was a significant difference in postoperative platelet counts between the infected and the noninfected splenectomy patients (P= 0.037), and a significant difference between splenectomy and control patients for white blood cell (WBC) counts (P = 0.007). Patients with splenectomy had higher precycle WBC, absolute neutrophil count (ANC), platelet counts, and higher postcycle nadir levels in all cycles compared to control patients. There was a significant overall difference between splenectomy patients and controls with regard to WBC (P = 0.001), ANC (P = 0.005), and platelet counts (P = 0.016) during chemotherapy cycles. Median postchemotherapy nadir WBC was 4.4 (range: 3.4-4.8) for the splenectomy group versus 2.8 (range: 2.5-3.0) for the control group. Median postchemotherapy nadir ANC was 1800 (range: 1320-2450) for the splenectomy group and 1001 (range: 864-1064) for the control group. Median postchemotherapy nadir platelet count was 222 (range: 181-277) for the splenectomy patients and 169 (range 164-215) for the control patients. In conclusion, the patients who undergo splenectomy as part of cytoreductive surgeries have a statistically significant leukocytosis and insignificant thrombocytosis relative to the control patients. Leukocytosis alone is not an accurate indicator of infection. Splenectomy is not associated with an increased risk of chemotherapy-related neutropenia and thrombocytopenia.

Adult↗
PubMed1982

Two additional cases of coexisting polycythaemia vera and chronic lymphocytic leukaemia.

2 patients with coexistent polycythaemia vera and chronic lymphocytic leukaemia are described. A 61-year-old man presented with an increased packed cell volume (PCV) and a leucoerythroblastic blood picture, which was reversible upon treatment, neutrophil leucoytosis, bone marrow lymphocyte infiltration and splenomegaly, and subsequently developed lymphomas, blood lymphocytosis and thrombocytosis. The second case was a 58-year-old female presenting with increased PCV and leucocyte alkaline phosphatase score. She later had neutrophil leucocytosis, thrombocytosis, lymphocytosis, lymphomas and splenomegaly. These cases, together with 6 cases published by others, suggest that an association exists between the two diseases.

Erythropoietin↗
PubMed1985

Relationship of mean platelet volume to platelet count in morphologic evaluation of thrombopoiesis.

A graph of the relationship between mean platelet volume (MPV) and platelet count (TPK) was constructed out of 158 haematologically normal individuals, 19 patients with thrombocytopenia and 63 patients with thrombocytosis. Patients with thrombocytopenia and thrombocytosis whose bone marrows were found to show adequate or increased, morphologically normal, thrombopoiesis were included in the graph. The graph was found to exhibit the previously known inverse relationship between TPK and MPV extended into thrombocytopenic values and is thought to represent an intact marrow function capable of meeting the increased demands of thrombopoiesis. On the other hand, 15 patients whose bone marrows were showing evidence of hypoplastic thrombopoiesis fell outside the region representing intact marrow function. The position of an individual's values of MPV vs TPK in a coordinate system with these variables on the axes correlates well with the morphologic evaluation of thrombopoietic function and seems to be clinically useful.

Blood Platelets↗
PubMed1989

Qualitative platelet defects in chronic myeloproliferative disorders: evidence for reduced ATP secretion.

19 consecutive untreated patients with chronic myeloproliferative disorders and thrombocytosis were subjected to comprehensive platelet function tests including platelet aggregometry. 12 patients had essential thrombocythaemia (ET) and 7 patients had polycythaemia vera (PV). Bleeding time was normal. Arachidonic acid, collagen and ristocetin aggregation were abnormal only in a minority of patients, whereas ADP aggregation was impaired in 16 out of 19 patients. The most conspicuous findings were abolished second-wave adrenalin aggregation, increased ADP aggregation threshold, and markedly reduced ATP secretion during collagen-induced aggregation. This triad of qualitative platelet defects seems to be a good diagnostic marker of chronic myeloproliferative disease with thrombocytosis.

Adenosine Diphosphate↗
PubMed1993

Measurement of spleen size using gamma camera scintigraphy in essential thrombocythaemia.

By using gamma camera imaging the spleen size was determined in 33 consecutive patients with essential thrombocythaemia (ET) and in 33 consecutive patients with reactive thrombocytosis (RT). All ET patients were newly diagnosed and had not received myelosuppressive treatment prior to study; they all fulfilled the criteria for ET as established by the Polycythemia Vera Study Group. In both posterior and lateral projections, the spleen area in the group of ET patients was significantly larger than in the RT patients. The present study has shown that 39% of ET patients at diagnosis have splenic enlargement. Evaluation of spleen size is therefore a useful diagnostic test in patients presenting with unexplained thrombocytosis.

Adult↗
PubMed2005

Long-term analysis of the palliative benefit of 2-chlorodeoxyadenosine for myelofibrosis with myeloid metaplasia.

OBJECTIVE: Therapeutic splenectomy in myelofibrosis with myeloid metaplasia (MMM) may result in extreme thrombocytosis and leukocytosis and accelerated hepatomegaly. We previously described initial palliative benefit from 2-chlorodeoxyadenosine (2-CdA) in such instances. The purpose of this study is to provide long-term follow-up on the durability of response in the initial cohort and in additional subsequent cases. METHODS: We retrospectively identified patients with histologically confirmed MMM who had palliative therapy with 2-CdA. Clinical characteristics and information on subsequent clinical course were abstracted at the time of diagnosis of MMM and at initiation of 2-CdA therapy until death. RESULTS: To date, we have used 2-CdA as palliative therapy in 14 patients with MMM. After a median of four cycles of therapy, responses for hepatomegaly occurred in 56% of patients, thrombocytosis 50%, leukocytosis 55%, and anemia 40%. Cytopenias were frequent but usually transient and without clinical consequence. Responses occurred usually by the second cycle; median duration of response was 6 months (range, 2-19) after completion of 2-CdA therapy. CONCLUSION: This study confirmed relevant and frequently durable palliation of symptoms in about half the patients. 2-CdA is a reasonable palliative option in postsplenectomy patients with MMM who have problematic myeloproliferation.

Adult↗
PubMed1990

DNA content and nuclear size of megakaryocytes in thrombocythaemia.

Total nuclear DNA content and nuclear size of megakaryocytes were studied in biopsies of the iliac bone marrow of individuals with normal or increased platelet counts. The DNA content was determined using Feulgen cytophotometry of bone marrow smears and the nuclear area by morphometric analysis of megakaryocytes of bone marrow sections. The mean DNA content and the mean nuclear area were both significantly larger in megakaryocytes of patients with thrombocytosis as a result of myeloproliferative disease than in patients with secondary thrombocytosis as well as in two control groups of individuals with normal platelets counts, one comprising healthy volunteers, the other with various non-haematological disorders. There was a statistically significant correlation between the DNA content and nuclear area of the megakaryocytes (r = 0.92) in the entire group of bone marrows studied.

Adolescent↗
PubMed1999

Diagnostic and hematologic features of probable essential thrombocythemia in two dogs.

The clinical and hematologic features of two cases of probable essential thrombocythemia in the dog are described. Both dogs presented with hepatosplenomegaly, severe nonregenerative anemia, neutrophilia and Thrombocytosis. Mean platelet volume and percentages of large platelets were markedly increased in both dogs. Platelet aggregation studies demonstrated hyperaggregability in one dog; platelets from the other dog aggregated spontaneously, precluding further investigation. Cytologic and histologic examination of bone marrow showed pronounced megakaryocytic hyperplasia, with erythroid hypoplasia and relative myeloid hyperplasia. Megakaryocyte morphology was abnormal, with increased numbers of small mononuclear and binucleate cells. Normal to increased hemosiderin stores suggested that apparent macrocytosis in one dog, rather than being due to iron deficiency, resulted from the hematology analyzer counting large platelets as small red blood cells. Megakaryocytic infiltration of the spleen was evident in both dogs. The hematologic findings in dogs with essential thrombocythemia can mimic those associated with iron deficiency anemia, such that diagnostic investigations should be aimed at ruling out chronic blood loss and other causes of reactive Thrombocytosis.

Journal Article↗
PubMedDate not supplied

Probable essential thrombocythemia in a dog.

Essential thrombocythemia (ET) in an 11-year-old dog was characterized by persistently high platelet counts (range, 4.19 X 10(6)/microliters to 4.95 X 10(6)/microliters, abnormal platelet morphology, marked megakaryocytic hyperplasia in the bone marrow, absence of circulating megakaryoblasts, and history of splenomegaly and gastrointestinal bleeding. Increased numbers of megakaryocytes and megakaryoblasts (15% to 20%) in the bone marrow were confirmed by a positive acetylcholinesterase reaction. Another significant finding was the presence of a basophilia in blood (4,836/microliters) and bone marrow. The marked persistent thrombocytosis, absence of reactive (secondary) thrombocytosis, abnormal platelet morphology, and quantitative and qualitative changes in the megakaryocytic series in the bone marrow suggested the presence of a myeloproliferative disease. Cytochemical and ultrastructural findings aided in the diagnosis of ET. The dog was treated with radiophosphorus. The results was a rapid decline in the numbers of megakaryoblasts and megakaryocytes in the bone marrow and platelets and basophils in the peripheral blood. The dog died unexpectedly of acute necrotizing pancreatitis and diabetes mellitus before a complete remission was achieved.

Animals↗
PubMed1986

Thrombopoietic activity in preterm newborns and infants.

Platelet count and thrombopoietic activity were investigated in preterm infants at birth and during their first four months of life. Thrombopoiesis stimulating factor activity in cord serum was significantly lower than that of adults and of the respective mothers. No difference was noted between thrombopoietic activity in cord serum in the various gestational ages studied--that is, 24 through 39 weeks. Preterm infants followed during their first four months of life showed a mean platelet count significantly higher than that observed in term infants at the respective age. Furthermore, thrombocytosis was found in premature thriving infants at the age of 1 and 2 months. It is suggested that this thrombocytosis is responsible for the low thrombopoietic activity observed in these infants during their first four months of life.

Adult↗